DESCRIPTION (Investigator's Abstract): Our long-term goal is to understand the specific changes in brain of patients with dominantly a inherited olivopontocerebellar atrophy [OPCA) responsible for the neurobehavioural disturbances and the etiology of this condition. This will be achieved through an intensive multidisciplinary approach involving annual neurological and neuropsychological assessment of 30 U.s. OPCA patients and, at autopsy follow-up, postmortem brain neurochemical and neuropathological analyses. Our specific aims are to: 1) define the role of brain cholinergic system dysfunction in the cognitive deficits of OPCA; 2) determine the biochemical factors which might cause OPCA through examination in postmortem brain of phospholipid and energy metabolic processes, and programmed cell death mechanisms; 3) establish OPCA as a model of early nigrostriatal dopamine neurone degeneration and 4) improve the life of the OPCA patient through dvsohaaia intervention. We expect that these studies will identify processes involved in the brain degeneration of OPCA as well as the brain structures responsible for the cognitive impairment of this disorder which, in some patients, is an important clinical management issue. The obtained results are also likely to be relevant to brain pathophysiological processes in other spino cerebellar ataxia disorders and in more common human brain conditions [Alzheimer's disease, Parkinson's disease, normal aging) which share with OPCA certain biochemical features.